Migration of medial smooth muscle cells (SMC) into the intima in response to vascular injury is a major component of the remodeling which occurs in the development of atherosclerotic and restonotic lesions. Growth factors such as PDGF and the neurotrophins, which activate the PDGF and trk receptor tyrosine kinases, respectively, are potent chemotactic agents for vascular SMC. Cellular migration is highly regulated, requiring first, the detachment of cells from the extracellular matrix, followed by the reorganization of the cytoskeleton, and finally, the release of matrix, metalloproteinases, to degrade the basement membrane and permit SMC to egress from the media into the intima. The signaling mechanisms which coordinate the complex processes of cellular detachment, cytoskeletal reorganization and MMP release are poorly defined. The overall aim of this proposal is to dissect the downstream pathways regulating SMC migration in response to the neurotrophins and PDGF, and thus, determine if cellular or complementary signaling mechanisms are utilized by these two different receptor tyrosine kinases to induce directed cell migration. Specifically, we plan to: I. Identify signaling pathways activated by growth factors and adhesion molecules which initiate cellular detachment, cytoskeletal reorganization and turnover t focal adhesions in response to migratory stimuli. II. Identify the contributions of metalloproteinases in growth factor-initiate SMC migration. III. Directly evaluate the role of the neurotrophin, BDNF, on lesion development in well defined models of vascular injury. Lesion development in Apo E (-/-) mice deficient in either BDNF or the BDNF receptor, trk B, will be studied chronically in mice maintained on a high fat diet and acutely using the flow dependent-carotid artery ligation model off vascular injury. These studies will allow us to test whether impaired BDNF:trk B signaling reduces neointimal formation. These studies involve critical interactions with Dr. Roy Silverstein (Project III), Dr. Kathy Hajjar (Project II) and Dr. David Hajjar (Project VI).